A Ral Signalling Complex in Vesicle Traffic

囊泡运输中的 Ral 信号复合物

• 批准号: nhmrc : 272505
• 负责人: Prof Basil Roufogalis
• 金额: $ 32.11万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2004
• 资助国家: 澳大利亚
• 起止时间: 2004-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/ral-signalling-complex-vesicle-traffic/81776
• 关键词: Ral; Signalling; Complex; Vesicle; Traffic

Inside our cells is a complex traffic system. The vehicles are vesicles that come in different shapes and sizes and travel to specific destinations in the cell to deliver cargo such as: surface growth factor receptors that are to have their signalling terminated, proteins and lipids destined for the cell wall for growth or development (like neurite outgrowth) and proteins and hormones destined for secretion (like neurotransmitter release). More than 100 human genetic disorders map to defects in one of the components of this system. Proteins called small GTPases provide order for this traffic and allow specific cargo to reach specific destinations. They regulate cell functions by acting as switches, turning biochemical processes on and off inside the cell. Ral is a small GTPase enzyme found in brain and broadly distributed in other cells. We have discovered that Ral is part of a large signalling complex. When activated Ral stimulates effectors, either the exocyst or RalBP1. In turn, mild oxidative stress controls a Ral inhibitor protein called ERp57. The research proposed aims to establish the functional role for the Ral signalling complex in cells. We will determine with which vesicle trafficking events Ral is associated, which effector it utilises in that pathway, and how that effector directs the traffic. We will also map the steps that may lead to inactivation of Ral via ERp57 in cells, and propose that this is mediated by mild oxidative stress. Techniques of molecular biology, biochemistry, molecular biology, proteomics and microscopy will be used to establish these functions. The research will lead to increased knowledge of the significance of this protein to cellular and particularly neuronal cell function. This forms the basis for understanding normal cell function and for identification of further factors causing diseases of vesicle transport. In time, such research aids in the development of specific therapies for sufferers of such diseases.

在我们的细胞内是一个复杂的交通系统。这些载体是囊泡，它们具有不同的形状和大小，并在细胞中旅行到特定的目的地，以运送货物，例如：表面生长因子受体，它们的信号传导终止，蛋白质和脂质注定要进入细胞壁生长或发育（如神经突生长），蛋白质和激素注定要分泌（如神经递质释放）。超过100种人类遗传疾病都与该系统的一个组成部分的缺陷有关。被称为小GTP酶的蛋白质为这种运输提供秩序，并允许特定的货物到达特定的目的地。它们通过充当开关来调节细胞功能，打开和关闭细胞内的生化过程。Ral是一种在大脑中发现并广泛分布于其他细胞中的小G T β酶。我们发现Ral是一个大型信号复合体的一部分。当激活Ral刺激效应器时，外囊或RalBP 1。反过来，轻度氧化应激控制一种称为ERp57的Ral抑制蛋白。这项研究旨在确定Ral信号复合物在细胞中的功能作用。我们将确定与哪些囊泡贩运事件Ral相关，它在该途径中使用哪个效应器，以及该效应器如何指导交通。我们还将绘制可能导致Ral通过ERp57在细胞中失活的步骤，并提出这是由轻度氧化应激介导的。将使用分子生物学、生物化学、分子生物学、蛋白质组学和显微镜技术来建立这些功能。这项研究将导致增加这种蛋白质对细胞，特别是神经元细胞功能的重要性的知识。这形成了理解正常细胞功能和鉴定引起囊泡运输疾病的其他因素的基础。随着时间的推移，这种研究有助于为这些疾病的患者开发特定的治疗方法。